tbuckley/cabot-search huggingface dataset:
Sports physiotherapists’ contribution to the sports and exercise medicine team: moving forward, together
Authors: Joanne Kemp, Luciana De Michelis Mendonça, Andrea Britt Mosler, Mario Bizzini, Kristian Thorborg, Fiona Wilson, Nicole Surdyka, Osman Hassan Ahmed, Nonhlanhla Sharon Mkumbuzi
Journal: British Journal of Sports Medicine (2022)
Multifocal Extramedullary Relapse With Neuroleukemiosis in a Case of Early T-Cell Precursor ALL
Authors: Abhiram G. Ashwathanarayana, Himanshu Bansal, Vikas Goyal, Vinita Dewangan
Journal: Clinical Nuclear Medicine (2022)

Early T-cell precursor ALL (acute lymphoblastic leukemia) is a rare type of childhood and adult T-cell ALL. Disease recurrence is common within 2 years from the time of initial diagnosis. Outcomes of relapse have been characterized through risk stratification schemes, and one of the major determinants of overall survival is the overall tumor burden and sites of relapse. Although testicular recurrence is common; Peripheral nerve as a site of recurrence is relatively rare. We present a case of early T-cell ALL on maintenance therapy with multifocal relapse on FDG PET/CT in the cervical lymph nodes, the testis, and the left sciatic nerve. Bone marrow and flow cytometry confirmed the relapse.
Bassoon contributes to tau-seed propagation and neurotoxicity
Authors: Pablo Martinez, Henika Patel, Yanwen You, Nur Jury, Abigail Perkins, Audrey Lee-Gosselin, Xavier Taylor, Yingjian You, Gonzalo Viana Di Prisco, Xiaoqing Huang, Sayan Dutta, Aruna B. Wijeratne, Javier Redding-Ochoa, Syed Salman Shahid, Juan F. Codocedo, Sehong Min, Gary E. Landreth, Amber L. Mosley, Yu-Chien Wu, David L. McKinzie, Jean-Christophe Rochet, Jie Zhang, Brady K. Atwood, Juan Troncoso, Cristian A. Lasagna-Reeves
Journal: Nature Neuroscience (2022)

Abstract Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.
Effective knowledge mobilisation: creating environments for quick generation, dissemination, and use of evidence
Authors: Raheelah Ahmad, Anthony C Gordon, Paul Aylin, Julian Redhead, Alison Holmes
Journal: BMJ (2022)

Effective response to the pandemic required real time use of research knowledge • Some existing infrastructures for generating and mobilising research findings accelerated collaborative working during the pandemic, and helped direct research appropriately • Investment is needed in integration of data, particularly for social care • Successful knowledge mobilisation needs to be sustained and expanded to support our recovery from the covid-19 pandemic and respond to further threatsThe simplest definition of knowledge mobilisation is the process of optimising the use of knowledge generated from research. 1 Connecting academic research with non-academic decision makers, including those involved in public policy and professional practice, is a complex process, but can be facilitated if problems are defined and solutions are tackled collaboratively.Knowledge mobilisation (the process) is focused on producing action that benefits society.It broadly encompasses dissemination, knowledge transfer, and knowledge exchange. 2 3Effective knowledge mobilisation occurs when research knowledge is perceived as relevant and usable and there is minimal duplication of effort through "unused" research findings. 4The covid-19 pandemic presented a previously unseen level of demand and urgency for research based evidence and for mechanisms to enable use of evidence almost in real time.The United Nations research roadmap for covid-19 recovery 5 puts knowledge mobilisation at the top of a list of required investments along with implementation science, rapid learning systems, scaling up data infrastructure, and the science of science. 5It is therefore important that the UK covid inquiry examines how knowledge was mobilised during the pandemic and what can be done to improve use of research evidence in future.
Compartmentalization of the host microbiome: how tumor microbiota shapes checkpoint immunotherapy outcome and offers therapeutic prospects
Authors: Maximilian Boesch, Lena Horvath, Florent Baty, Andreas Pircher, Dominik Wolf, Stephan Spahn, Ravid Straussman, Herbert Tilg, Martin H Brutsche
Journal: Journal for ImmunoTherapy of Cancer (2022)

The host microbiome is polymorphic, compartmentalized, and composed of distinctive tissue microbiomes. While research in the field of cancer immunotherapy has provided an improved understanding of the interaction with the gastrointestinal microbiome, the significance of the tumor-associated microbiome has only recently been grasped. This article provides a state-of-the-art review about the tumor-associated microbiome and sheds light on how local tumor microbiota shapes anticancer immunity and influences checkpoint immunotherapy outcome. The direct route of interaction between cancer cells, immune cells, and microbiota in the tumor microenvironment is emphasized and advocates a focus on the tumor-associated microbiome in addition to the spatially separated gut compartment. Since the mechanisms underlying checkpoint immunotherapy modulation by tumor-associated microbiota remain largely elusive, future research should dissect the pathways involved and outline strategies to therapeutically modulate microbes and their products within the tumor microenvironment. A more detailed knowledge about the mechanisms governing the composition and functional quality of the tumor microbiome will improve cancer immunotherapy and advance precision medicine for solid tumors.
Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer
Authors: Stephanie Gomez, Olivia L Cox, Reddick R Walker, Uzma Rentia, Melissa Hadley, Elisa Arthofer, Noor Diab, Erin E Grundy, Tomas Kanholm, James I McDonald, Julie Kobyra, Erica Palmer, Satish Noonepalle, Alejandro Villagra, David Leitenberg, Catherine M Bollard, Yogen Saunthararajah, Katherine B Chiappinelli
Journal: Journal for ImmunoTherapy of Cancer (2022)

Novel therapies are urgently needed for ovarian cancer (OC), the fifth deadliest cancer in women. Preclinical work has shown that DNA methyltransferase inhibitors (DNMTis) can reverse the immunosuppressive tumor microenvironment in OC. Inhibiting DNA methyltransferases activate transcription of double-stranded (ds)RNA, including transposable elements. These dsRNAs activate sensors in the cytoplasm and trigger type I interferon (IFN) signaling, recruiting host immune cells to kill the tumor cells. Adenosine deaminase 1 (ADAR1) is induced by IFN signaling and edits mammalian dsRNA with an A-to-I nucleotide change, which is read as an A-to-G change in sequencing data. These edited dsRNAs cannot be sensed by dsRNA sensors, and thus ADAR1 inhibits the type I IFN response in a negative feedback loop. We hypothesized that decreasing ADAR1 editing would enhance the DNMTi-induced immune response.Human OC cell lines were treated in vitro with DNMTi and then RNA-sequenced to measure RNA editing. Adar1 was stably knocked down in ID8 Trp53-/- mouse OC cells. Control cells (shGFP) or shAdar1 cells were tested with mock or DNMTi treatment. Tumor-infiltrating immune cells were immunophenotyped using flow cytometry and cell culture supernatants were analyzed for secreted chemokines/cytokines. Mice were injected with syngeneic shAdar1 ID8 Trp53-/- cells and treated with tetrahydrouridine/DNMTi while given anti-interferon alpha and beta receptor 1, anti-CD8, or anti-NK1.1 antibodies every 3 days.We show that ADAR1 edits transposable elements in human OC cell lines after DNMTi treatment in vitro. Combining ADAR1 knockdown with DNMTi significantly increases pro-inflammatory cytokine/chemokine production and sensitivity to IFN-β compared with either perturbation alone. Furthermore, DNMTi treatment and Adar1 loss reduces tumor burden and prolongs survival in an immunocompetent mouse model of OC. Combining Adar1 loss and DNMTi elicited the most robust antitumor response and transformed the immune microenvironment with increased recruitment and activation of CD8+ T cells.In summary, we showed that the survival benefit from DNMTi plus ADAR1 inhibition is dependent on type I IFN signaling. Thus, epigenetically inducing transposable element transcription combined with inhibition of RNA editing is a novel therapeutic strategy to reverse immune evasion in OC, a disease that does not respond to current immunotherapies.
Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial
Authors: Alexandre Mebazaa, Beth Davison, Ovidiu Chioncel, Alain Cohen-Solal, Rafael Diaz, Gerasimos Filippatos, Marco Metra, Piotr Ponikowski, Karen Sliwa, Adriaan A Voors, Christopher Edwards, Maria Novosadova, Koji Takagi, Albertino Damasceno, Hadiza Saidu, Etienne Gayat, Peter S Pang, Jelena Celutkiene, Gad Cotter
Journal: The Lancet (2022)
Correction: Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency
Authors: Tessa Mollie Campbell, Zhiyong Liu, Qian Zhang, Marcela Moncada-Velez, Laura E. Covill, Peng Zhang, Ilad Alavi Darazam, Paul Bastard, Lucy Bizien, Giorgia Bucciol, Sara Lind Enoksson, Emmanuelle Jouanguy, Şemsi Nur Karabela, Taushif Khan, Yasemin Kendir-Demirkol, Andres Augusto Arias, Davood Mansouri, Per Marits, Nico Marr, Isabelle Migeotte, Leen Moens, Tayfun Ozcelik, Isabelle Pellier, Anton Sendel, Sevtap Şenoğlu, Mohammad Shahrooei, C.I. Edvard Smith, Isabelle Vandernoot, Karen Willekens, Kadriye Kart Yaşar, Peter Bergman, Laurent Abel, Aurélie Cobat, Jean-Laurent Casanova, Isabelle Meyts, Yenan T. Bryceson
Journal: The Journal of Experimental Medicine (2022)
Indole intercepts the communication between enteropathogenic <i>E. coli</i> and <i>Vibrio cholerae</i>
Authors: Orna Gorelik, Alona Rogad, Lara Holoidovsky, Michael M. Meijler, Neta Sal-Man
Journal: Gut Microbes (2022)

Reported numbers of diarrheal samples exhibiting co-infections or multiple infections, with two or more infectious agents, are rising, likely due to advances in bacterial diagnostic techniques. Bacterial species detected in these samples include Vibrio cholerae (V. cholerae) and enteropathogenic Escherichia coli (EPEC), which infect the small intestine and are associated with high mortality rates. It has previously been reported that EPEC exhibit enhanced virulence in the presence of V. cholerae owing to their ability to sense and respond to elevated concentrations of cholera autoinducer 1 (CAI-1), which is the primary quorum-sensing (QS) molecule produced by V. cholerae. In this study, we examined this interspecies bacterial communication in the presence of indole, a major microbiome-derived metabolite found at high concentrations in the human gut. Interestingly, we discovered that although indole did not affect bacterial growth or CAI-1 production, it impaired the ability of EPEC to enhance its virulence activity in response to the presence of V. cholerae. Furthermore, the co-culture of EPEC and V. cholerae in the presence of B. thetaiotaomicron, an indole-producing commensal bacteria, ablated the enhancement of EPEC virulence. Together, these results suggest that microbiome compositions or diets that influence indole gut concentrations may differentially impact the virulence of pathogens and their ability to sense and respond to competing bacteria.
Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis
Authors: Masato Ogishi, Rui Yang, Rémy Rodriguez, Dominic P. Golec, Emmanuel Martin, Quentin Philippot, Jonathan Bohlen, Simon J. Pelham, Andrés Augusto Arias, Taushif Khan, Manar Ata, Fatima Al Ali, Flore Rozenberg, Xiao-Fei Kong, Maya Chrabieh, Candice Laine, Wei-Te Lei, Ji Eun Han, Yoann Seeleuthner, Zenia Kaul, Emmanuelle Jouanguy, Vivien Béziat, Leila Youssefian, Hassan Vahidnezhad, V. Koneti Rao, Bénédicte Neven, Claire Fieschi, Davood Mansouri, Mohammad Shahrooei, Sevgi Pekcan, Gulsum Alkan, Melike Emiroğlu, Hüseyin Tokgöz, Jouni Uitto, Fabian Hauck, Jacinta Bustamante, Laurent Abel, Sevgi Keles, Nima Parvaneh, Nico Marr, Pamela L. Schwartzberg, Sylvain Latour, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis
Journal: The Journal of Experimental Medicine (2022)

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4−CD8− double-negative (DN) αβ and Vδ2− γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES− phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients’ T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients’ total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ–producing T cell subsets, thereby underlying TB.
N1-methyladenosine formation, gene regulation, biological functions, and clinical relevance
Authors: Weidong Xiong, Yongchao Zhao, Zilun Wei, Chaofu Li, Ranzun Zhao, Junbo Ge, Bei Shi
Journal: Molecular Therapy (2022)

N1-methyladenosine (m1A) is an adenosine moiety whose N1-position is methylated. m1A methylation is a prevalent, abundant, and conserved internal post-transcriptional modification among prokaryotic and eukaryotic RNAs, especially in higher eukaryotic cells. Numerous studies have revealed that m1A methylation plays a critical role in the biogenesis of various RNAs, thereby regulating different biological functions and pathogenesis. In this review, we systematically and comprehensively summarize the installation, removal, and recognition of m1A and highlight the critical effects of m1A on the post-transcriptional metabolism of various RNAs. We emphasize the importance of m1A both in the growth of organisms and pathogenesis of various diseases, particularly cancers. Finally, we also focused on the fact that excretion of m1A in human urine is strongly associated with the progression of a variety of diseases, and we suggest that m1A levels in urine can be quantified for early diagnosis of some diseases as well as for monitoring during disease evolution.
Comorbidity defines asthmatic patients' risk of COVID-19 hospitalization: A global perspective
Authors: Chrysanthi Skevaki, R. Sharon Chinthrajah, Daria Fomina, Gernot Rohde, Shu Cao, Ziyuan He, Sofia Serdotetskova, Christian Seidemann, Achim Grünewaldt, Abisha Vengadeswaran, Min Xie, Antonina Karsonova, Alexander Karaulov, Kari C. Nadeau, Ho-Ryun Chung, Harald Renz
Journal: Journal of Allergy and Clinical Immunology (2022)
Role of protein phosphorylation in cell signaling, disease, and the intervention therapy
Authors: Kun Pang, Wei Wang, Jia‐Xin Qin, Zhen‐Duo Shi, Lin Hao, Yu‐Yang Ma, Hao Xu, Zhuo‐Xun Wu, Deng Pan, Zhe‐Sheng Chen, Cong‐Hui Han
Journal: MedComm (2022)

Abstract Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and C dc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.
Inside the stemness engine: Mechanistic links between deregulated transcription factors and stemness in cancer
Authors: Egle-Helene Ervin, Rhiannon French, Chao-Hui Chang, Siim Pauklin
Journal: Seminars in Cancer Biology (2022)

Cell identity is largely determined by its transcriptional profile. In tumour, deregulation of transcription factor expression and/or activity enables cancer cell to acquire a stem-like state characterised by capacity to self-renew, differentiate and form tumours in vivo. These stem-like cancer cells are highly metastatic and therapy resistant, thus warranting a more complete understanding of the molecular mechanisms downstream of the transcription factors that mediate the establishment of stemness state. Here, we review recent research findings that provide a mechanistic link between the commonly deregulated transcription factors and stemness in cancer. In particular, we describe the role of master transcription factors (SOX, OCT4, NANOG, KLF, BRACHYURY, SALL, HOX, FOX and RUNX), signalling-regulated transcription factors (SMAD, β-catenin, YAP, TAZ, AP-1, NOTCH, STAT, GLI, ETS and NF-κB) and unclassified transcription factors (c-MYC, HIF, EMT transcription factors and P53) across diverse tumour types, thereby yielding a comprehensive overview identifying shared downstream targets, highlighting unique mechanisms and discussing complexities.
Comparative Safety and Effectiveness of Biologic Therapy for Crohn’s Disease: A CA-IBD Cohort Study
Authors: Siddharth Singh, Jihoon Kim, Jiyu Luo, Paulina Paul, Vivek Rudrapatna, Sunhee Park, Kai Zheng, Gaurav Syal, Christina Ha, Phillip Fleshner, Dermot McGovern, Jenny S. Sauk, Berkeley Limketkai, Parambir S. Dulai, Brigid S. Boland, Samuel Eisenstein, Sonia Ramamoorthy, Gil Melmed, Uma Mahadevan, William J. Sandborn, Lucila Ohno-Machado
Journal: Clinical Gastroenterology and Hepatology (2022)
Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner
Authors: Tina Schumann, Santiago Costas Ramon, Nadja Schubert, Mohamad Aref Mayo, Melanie Hega, Katharina Isabell Maser, Servi-Remzi Ada, Lukas Sydow, Mona Hajikazemi, Markus Badstübner, Patrick Müller, Yan Ge, Farhad Shakeri, Andreas Buness, Benjamin Rupf, Stefan Lienenklaus, Barbara Utess, Lina Muhandes, Michael Haase, Luise Rupp, Marc Schmitz, Thomas Gramberg, Nicolas Manel, Gunther Hartmann, Thomas Zillinger, Hiroki Kato, Stefan Bauer, Alexander Gerbaulet, Katrin Paeschke, Axel Roers, Rayk Behrendt
Journal: The Journal of Experimental Medicine (2022)

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon–driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.
Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection
Authors: Man-Fung Yuen, Seng-Gee Lim, Robert Plesniak, Keiji Tsuji, Harry L.A. Janssen, Cristina Pojoga, Adrian Gadano, Corneliu P. Popescu, Tatyana Stepanova, Tarik Asselah, Gheorghe Diaconescu, Hyung Joon Yim, Jeong Heo, Ewa Janczewska, Alexander Wong, Nevin Idriz, Michio Imamura, Giuliano Rizzardini, Koichi Takaguchi, Pietro Andreone, Manuela Arbune, Jinlin Hou, Sung Jae Park, Andrei Vata, Jennifer Cremer, Robert Elston, Tamara Lukić, Geoff Quinn, Lauren Maynard, Stuart Kendrick, Helene Plein, Fiona Campbell, Melanie Paff, Dickens Theodore
Journal: New England Journal of Medicine (2022)

Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.
A Modern Therapy for an Ancient Disease
Authors: Jay H. Hoofnagle
Journal: New England Journal of Medicine (2022)

Chronic infection with the hepatitis B virus (HBV) affects 4% of the population worldwide and accounts for more than a half million deaths yearly.1 An ancient disease, perhaps dating before anatomically modern humans left Africa,2 chronic hepatitis B is present in virtually all populations on Earth. The highest prevalences are found in Asia and Africa, whereas the prevalence in the United States (0.3%) is among the lowest.3 The control and ultimate elimination of HBV will depend on wide-scale use of the HBV vaccine. In the United States, universal childhood HBV vaccination was initiated in 1991 and has now made hepatitis . . .